Sustained effects of repeated levodopa (L-DOPA) administration on reward circuitry, effort-based motivation, and anhedonia in depressed patients with higher inflammation.

Inflammatory biomarkers like C-reactive protein (CRP) are elevated in a subset of patients with depression and associated with lower functional connectivity (FC) in a ventral striatum (VS) to ventromedial prefrontal cortex (vmPFC) reward circuit and symptoms of anhedonia. Evidence linking these relationships to the effects of inflammation on dopamine is consistent with our recent findings that acute levodopa (L-DOPA) increased VS-vmPFC FC in association with deceased anhedonia in depressed patients with higher but not lower CRP (>2 versus ≤ 2 mg/L). To determine whether repeated L-DOPA administration caused sustained effects on FC and behavior in these patients, medically stable depressed outpatients with CRP > 2 mg/L and anhedonia (n = 18) received one week of three doses of L-DOPA (150-450 mg/day/week with carbidopa) or placebo in a randomized order.

DNA methylation profiles of cancer-related fatigue associated with markers of inflammation and immunometabolism.

Cancer patients are commonly affected by fatigue. Herein, we sought to examine epigenetic modifications (i.e.

C-reactive protein moderates associations between racial discrimination and ventromedial prefrontal cortex activation during attention to threat in Black American women.

Prior research has shown that racial discrimination (RD) impacts activation in threat network regions, including the ventromedial prefrontal cortex (vmPFC) and middle occipital cortex during attention to threat-relevant stimuli. However, little is known about the biological mechanisms that may modulate these effects; inflammation may be a pathway linking RD and threat network activation. As such, the current study aimed to explore whether systemic inflammation, measured by C-reactive protein (CRP) levels, may moderate the relationship between RD and activation in the vmPFC and middle occipital cortex during attention to threat.

Associations of inflammation with neuropsychological symptom cluster in patients with Head and neck cancer: A longitudinal study.

Purpose: Head and neck cancer (HNC) patients may experience multiple co-occurring neuropsychological symptoms (NPS) cluster, including fatigue, depression, pain, sleep disturbance, and cognitive impairment. While inflammation has been attributed as a key mechanism for some of these symptoms, its association with the NPS as a cluster of symptoms is unknown. Thus, the aim of this study was to examine the association between peripheral inflammation and NPS cluster among HNC patients over cancer treatment (radiotherapy with or without chemotherapy).

Cerebrospinal fluid levels of 5-HIAA and dopamine in people with HIV and depression.

Depression is a common illness in people with HIV (PWH) and is associated with substantial morbidity and mortality. The mechanisms that underpin depression in PWH remain incompletely elucidated, and more research is therefore needed to develop effective treatments. One hypothesis is that neurotransmitter levels may be altered.

Longitudinal associations among physical activity, inflammatory markers, and quality of life in patients with head and neck cancer.

Introduction: The aim of this study was to explore the associations among physical activity (PA), inflammatory markers, and quality of life (QoL) from preradiotherapy to 1-year postradiotherapy for patients with head and neck cancer (HNC).

Methods: This was an observational longitudinal study. Mixed-effect models incorporating within-subject correlation were used to examine the relationship among the three key variables.

Increased Inflammation and Treatment of Depression: From Resistance to Reuse, Repurposing, and Redesign.

Based on mounting clinical and translational evidence demonstrating the impact of exogenously administered inflammatory stimuli on the brain and behavior, increased endogenous inflammation has received attention as one pathophysiologic process contributing to psychiatric illnesses and particularly depression. Increased endogenous inflammation is observed in a significant proportion of depressed patients and has been associated with reduced responsiveness to standard antidepressant therapies. This chapter presents recent evidence that inflammation affects neurotransmitters and neurocircuits to contribute to specific depressive symptoms including anhedonia, motor slowing, and anxiety, which may preferentially improve after anti-cytokine therapies in patients with evidence of increased inflammation.

Inflammation-Related Functional and Structural Dysconnectivity as a Pathway to Psychopathology.

Findings from numerous laboratories and across neuroimaging modalities have consistently shown that exogenous administration of cytokines or inflammatory stimuli that induce cytokines disrupts circuits and networks involved in motivation and motor activity, threat detection, anxiety, and interoceptive and emotional processing. While inflammatory effects on neural circuits and relevant behaviors may represent adaptive responses promoting conservation of energy and heightened vigilance during immune activation, chronically elevated inflammation may contribute to symptoms of psychiatric illnesses. Indeed, biomarkers of inflammation such as cytokines and acute phase reactants are reliably elevated in a subset of patients with unipolar or bipolar depression, anxiety-related disorders, and schizophrenia and have been associated with differential treatment responses and poor clinical outcomes.

Clinical response to EPA supplementation in patients with major depressive disorder is associated with higher plasma concentrations of pro-resolving lipid mediators.

Chronic inflammation has been implicated in the pathophysiology of major depressive disorder (MDD). Activating the resolution of inflammation through ω-3 fatty acid supplementation may prove to be a successful therapeutic strategy for the treatment of MDD. Patients with MDD, body mass index >25 kg/m, and plasma high-sensitivity C-reactive protein ≥3 μg/mL (n = 61) were enrolled in a 12-week randomized trial consisting of 4 parallel arms: EPA 1, 2, and 4 g/d, and placebo.

Omega-3 Fatty Acids for Major Depressive Disorder With High Inflammation: A Randomized Dose-Finding Clinical Trial.

This study compared the impact of 3 eicosapentaenoic acid (EPA) doses versus placebo on inflammatory biomarkers and depressive symptoms. Sixty-one unmedicated adults (75% female; 45.5 ± 13.

Functional connectivity in reward circuitry and symptoms of anhedonia as therapeutic targets in depression with high inflammation: evidence from a dopamine challenge study.

Increased inflammation in major depressive disorder (MDD) has been associated with low functional connectivity (FC) in corticostriatal reward circuits and symptoms of anhedonia, relationships which may involve the impact of inflammation on synthesis and release of dopamine. To test this hypothesis while establishing a platform to examine target engagement of potential therapies in patients with increased inflammation, medically stable unmedicated adult MDD outpatients enrolled to have a range of inflammation (as indexed by plasma C-reactive protein [CRP] levels) were studied at two visits involving acute challenge with the dopamine precursor levodopa (L-DOPA; 250 mg) and placebo (double-blind, randomized order ~1-week apart). The primary outcome of resting-state (rs)FC in a classic ventral striatum to ventromedial prefrontal cortex reward circuit was calculated using a targeted, a priori approach.

The role of the immune system in posttraumatic stress disorder.

Posttraumatic stress disorder (PTSD) develops in a subset of individuals upon exposure to traumatic stress. In addition to well-defined psychological and behavioral symptoms, some individuals with PTSD also exhibit elevated concentrations of inflammatory markers, including C-reactive protein, interleukin-6, and tumor necrosis factor-α. Moreover, PTSD is often co-morbid with immune-related conditions, such as cardiometabolic and autoimmune disorders.

Inflammation, amygdala-ventromedial prefrontal functional connectivity and symptoms of anxiety and PTSD in African American women recruited from an inner-city hospital: Preliminary results.

Inflammatory stimuli have been shown to impact brain regions involved in threat detection and emotional processing including amygdala and ventromedial prefrontal cortex (vmPFC), and to increase anxiety. Biomarkers of endogenous inflammation, including inflammatory cytokines and C-reactive protein (CRP), are reliably elevated in a subset of patients with depression and anxiety-related disorders such as post-traumatic stress disorder (PTSD), and have been associated with high anxiety in population studies. We previously reported that plasma CRP and cytokines in patients with depression were negatively correlated with resting-state functional connectivity (FC) between right amygdala and vmPFC, as assessed using both ROI to voxel-wise and targeted FC approaches, in association with symptoms of anxiety, particularly in patients with comorbid anxiety disorders or PTSD.

Cellular and immunometabolic mechanisms of inflammation in depression: Preliminary findings from single cell RNA sequencing and a tribute to Bruce McEwen.

Inflammation is associated with symptoms of anhedonia, a core feature of major depression (MD). We have shown that MD patients with high inflammation as measured by plasma C-reactive protein (CRP) and anhedonia display gene signatures of metabolic reprograming (e.g.

Inflammation as a Pathophysiologic Pathway to Anhedonia: Mechanisms and Therapeutic Implications.

Anhedonia, characterized by a lack of motivation, interest, or ability to experience pleasure, is a prominent symptom of depression and other psychiatric disorders and has been associated with poor response to standard therapies. One pathophysiologic pathway receiving increased attention for its potential role in anhedonia is inflammation and its effects on the brain. Exogenous administration of inflammatory stimuli to humans and laboratory animals has reliably been found to affect neurotransmitters and neurocircuits involved in reward processing, including the ventral striatum and ventromedial prefrontal cortex, in association with reduced motivation.

Transcriptomic signatures of psychomotor slowing in peripheral blood of depressed patients: evidence for immunometabolic reprogramming.

Inflammation impacts basal ganglia motor circuitry in association with psychomotor retardation, a key symptom of major depression (MD). We previously reported associations between circulating protein inflammatory biomarkers and psychomotor slowing as measured by neuropsychological tests probing psychomotor speed in patients with MD. To discover novel transcriptional signatures in peripheral blood immune cells related to psychomotor slowing, microarray data were analyzed in a primary cohort of 88 medically-stable, unmedicated, ambulatory MD patients.

Kynurenines increase MRS metabolites in basal ganglia and decrease resting-state connectivity in frontostriatal reward circuitry in depression.

Inflammation is associated with the development of anhedonia in major depression (MD), but the pathway by which inflammatory molecules gain access to the brain and lead to anhedonia is not clear. Molecules of the kynurenine pathway (KP), which is activated by inflammation, readily influx into the brain and generate end products that alter brain chemistry, disrupt circuit functioning, and result in the expression of inflammatory behaviors such as anhedonia. We examined the impact of plasma and CSF KP metabolites on brain chemistry and neural function using multimodal neuroimaging in 49 depressed subjects.

Influences of dopaminergic system dysfunction on late-life depression.

Deficits in cognition, reward processing, and motor function are clinical features relevant to both aging and depression. Individuals with late-life depression often show impairment across these domains, all of which are moderated by the functioning of dopaminergic circuits. As dopaminergic function declines with normal aging and increased inflammatory burden, the role of dopamine may be particularly salient for late-life depression.

Aiding and Abetting Anhedonia: Impact of Inflammation on the Brain and Pharmacological Implications.

Exogenous administration of inflammatory stimuli to humans and laboratory animals and chronic endogenous inflammatory states lead to motivational deficits and ultimately anhedonia, a core and disabling symptom of depression present in multiple other psychiatric disorders. Inflammation impacts neurotransmitter systems and neurocircuits in subcortical brain regions including the ventral striatum, which serves as an integration point for reward processing and motivational decision-making. Many mechanisms contribute to these effects of inflammation, including decreased synthesis, release and reuptake of dopamine, increased synaptic and extrasynaptic glutamate, and activation of kynurenine pathway metabolites including quinolinic acid.

Dose- and time-dependent increase in circulating anti-inflammatory and pro-resolving lipid mediators following eicosapentaenoic acid supplementation in patients with major depressive disorder and chronic inflammation.

Background: Eicosapentaenoic acid (EPA) supplementation is an effective treatment option in major depressive disorder (MDD) associated with chronic low-grade inflammation. EPA is the precursor of specialized pro-resolving lipid mediators (SPMs) termed resolvins (Rv), that serve important roles in the resolution of inflammation. The objective of this study was to assess the effects of different doses of EPA on plasma concentrations of EPA metabolites and SPMs in MDD patients.